Cell and Tissue Journal

Abstract Introduction: Paxlovid, an investigational oral therapeutic combining the antiviral Nirmatrelvir and the pharmacokinetic enhancer Ritonavir, is being developed to treat SARS-CoV-2 infection, aiming to reduce severe disease progression, hospitalization, and mortality. While its efficacy has been shown in Phase 2/3 trials for non-hospitalized patients, its safety, particularly regarding fetal development, remains under investigation. Coronaviruses have long posed significant challenges to global public health, with their potential to cause severe respiratory infections in humans. Over the past two decades, two novel coronaviruses—Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV)—have emerged, leading to widespread morbidity and mortality. The SARS - CoV outbreak, which occurred in the early 2000s, infected over 8,000 individuals worldwide and resulted in nearly 800 deaths, representing a mortality rate of approximately 10 %. Similarly, MERS - CoV, identified in 2012, caused 857 confirmed infections and 3 34 deaths, with a strikingly high mortality rate of around 35 %. These outbreaks underscored the persistent threat posed by coronaviruses to human health.
Aims: Pregnant women represent a particularly vulnerable population during infectious disease outbreaks, and the potential teratogenic effects of new therapeutics must be carefully evaluated. Previous studies on Nirmatrelvir have explored its effects on skeletal morphogenesis, but comprehensive data on Paxlovid's impact on fetal development remain limited. This study aims to address this gap by investigating the effects of Paxlovid on the reproduction and skeletal morphogenesis of rat embryos, providing critical insights into its safety profile during pregnancy. By elucidating the potential risks associated with Paxlovid, this research contributes to the broader effort to ensure the safe use of antiviral therapies in vulnerable populations. This study assessed the potential embryotoxic effects of Paxlovid on rat fetal skeletal morphogenesis, following ICH guidelines.
Materials and methods: Pregnant rats were divided into four groups, receiving doses of 0, 100/60, 300/200, or 1000 mg/kg/day of Paxlovid. Maternal clinical symptoms and weight were monitored, and fetal outcomes, including weight, crown-rump length (CRL), and abdominal circumference (AC), were evaluated on gestational day 21. Histological analysis of fetal skeletal tissue was conducted using hematoxylin-eosin and Alizarin Red S staining to detect structural abnormalities.
Results: Results showed reduced maternal weight gain in Paxlovid-treated groups compared to controls. Fetuses in treated groups also exhibited lower weight, CRL, and AC. However, histological analysis revealed no structural abnormalities in skeletal tissue. These findings suggest that while Paxlovid may transiently affect fetal growth metrics, it does not induce teratogenic effects on skeletal development.
Discussion: The findings of this study revealed no histological abnormalities in the skeletal system of fetuses exposed to Paxlovid. The observed effects were limited to reductions in fetal weight, crown-rump length (CRL), and abdominal circumference (AC). Collectively, the data from this investigation, along with existing evidence, suggest a low risk of fetal harm associated with Paxlovid, which comprises Nirmatrelvir (NMV), a potent and selective inhibitor of the SARS-CoV-2 main protease, and Ritonavir, a pharmacokinetic enhancer. Nonetheless, the use of Paxlovid during pregnancy should be carefully evaluated, with a thorough discussion of potential risks and benefits conducted in consultation with a healthcare professional.
Conclusion: The study concludes that Paxlovid does not compromise the histological integrity of fetal skeletal tissue, supporting its potential safety during pregnancy. However, further research is needed to understand the mechanisms behind the observed growth effects and to confirm these findings in human populations. Overall, the results indicate a low risk of fetal harm, reinforcing Paxlovid's safety profile for use in pregnant individuals